FI61306B - SAOSOM SOETNINGSMEDEL ANVAENDBARA 1- (2-HYDROXY-4- (3-SULFOPROPYL-1-OXY) -PHENYL) -3- (3-HYDROXY-4-ALCOXIFENYL) -PROPAN-1-ONER SAMT DERAS SALTER - Google Patents

Description

rm Η-ν ANNOUNCEMENT. . _ Λ „LJ <11) UTLÄGGN INCSSKRIFT 6 1 3 Ο 6 • 2X5 C (45) Patin Ui issued on 12 07 1932

Patent teaser ^ (51) Kv.ik.Vci.3 C 07 C 143/11. 143/38.

A 23 I 1/236 FINLAND — FINLAND (21) Patent application - Patentansttknlnf 7501) 1) 2 (22) HakemlapUvt —Aneeknlnfadag 18.02.75 ^ * (23) Alkuptlvi — Glltlfhatsdaf 1Ö.02 75 (41) Tullut lulklaeksl —Bllvlt 08 75 FMenttl * and the Registry Board M4) NlhtMk.pMen |. kmilvlkataun pm. - rltant- OCn registorstyrclian AmOkut utlagd och utl.akrHten pubUcerad 03 82 (32) (33) (31) Requested privilege —Beflrd prloritet 19. Q2.7I)

Hungary-Hungary (HU) Cl-11) 1) 8 (71) Chinoin Pharmaceuticals and Chemicals Gyära Rt., To u. 1 to 5,

Budapest IV, Hungary-Hungary (HU) (72) Lorand Farkas, Budapest, Mihäly Nogrädi, Budapest, Todor Pfliegel,

Budapest, Sandor Antus, Budapest, Agnes Gottsegen, Budapest,

Hungary-Hungary (HU) (7M Oy Kolster Ab (5 ^) Sweeteners 1- (2-hydroxy-1) - (3-sulfopropyl-1-oxy) -phenyl) -3- (3-hydroxy-1) - Eloxyphenyl) propan-1-ones and their salts -propan-1-one, the same as the salt

The present invention relates to novel 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-alkoxyphenyl) -propan-1-ones useful as sweeteners of formula I

O

Tue

C - CH0 - CH0 OH

^ JX-XX “* 1? H2 CH- έθ3Η 2 wherein R * is ethyl or methyl, and their salts.

Calorie-free artificial sweeteners are of great importance for both diabetes and overweight healthy people. Saccharin and cyclamate are currently mainly used as sweeteners. Cyclamate is banned in some countries. Saccharin constantly loses its relevance due to its unpleasant aftertaste. Despite this, no equivalent sweeteners have been marketed to date. Numerous saccharin preparations are known which take advantage of the high sweetening power of saccharin. an unpleasant aftertaste has been tried to be prevented with sugar or other Kalo-flavored additives. For example, U.S. Pat. No. 3,743,518 describes a sweetener preparation consisting of 1 part by weight of saccharin-calcium or saccharin sodium, about 5 times by weight of fructose and 10-15 parts by weight of calcium or sodium gluconate or glucono-β-lactone, respectively. U.S. Patent 3,087,821 describes * hesperitine hydrocalcone glycoside as a very strong sweet flavoring compound suitable for artificial sweetener preparations.

The preparation of this compound from the hesperitin-like natural flavonone glycoside found in citrus species is protected by U.S. Patent 3,429,873. A highly specialized sweet flavor suggests that saccharine. The preparation of alkoxycarboxylic acid derivatives of dihydrocalcone and salts of these compounds is described in FI patent 58,489.

The compound of the FI patent, the sodium salt of 1- (3-hydroxy-4-carboxymethoxy-phenyl) -3- (3-hydroxy-4-methoxyphenyl) -propan-1-one, is 180 times sweeter than cane sugar and is soluble in cold water 20 times the amount.

The compound of the invention, the sodium salt of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) phenyl] -2- (3-hydroxy-4-methoxyphenyl) propan-1-one, has a sweetness compared to cane sugar , which, depending on the concentration, is 450-1200. The sweetness values of other salts, such as potassium and ammonium salts, are quite similar.

The compounds according to the invention are very soluble in, for example, water, heat and acid resistant and are non-toxic. Having a high sweetening power, they do not have an unpleasant off-flavor. They can be advantageously used in combination with additives, inactive salts or other sweeteners for sweetening foodstuffs and pharmaceutical preparations. Suitable additives are diluents, solvents, carriers, formulation auxiliaries and / or sweeteners.

3 61306

The compounds of the invention are prepared a) by reduction of the general formula (II)

O

C - CH = CH JOR

ry x £ ™ CH2 I 2 CHO SO3 M + 2, wherein R is as defined above and R is hydrogen or a hydrogenation-cleavable protecting group, preferably a benzyl or benzyloxycarbonyl group, and M + is a proton or other cation, or b) subjecting to the general formula compounds of formula (III) 2 in which R represents the same as above, preferably after protection of the hydroxy group in the 3-position of the ring, for the reaction of general formula (IV)

CH0 - SO- - X

I 2 2 (IV)

CH2 - CH2 - Y

wherein X is a group of the general formula O M + and Y is a halogen atom, or X and Y together represent an oxygen atom, or c) a compound of the general formula (V) 4 61306

O

. C-CH ~ -CH ~ OR1, -iX. XX. - compounds of the formula CH9 OR 1 * CH_SO 3 M +, in which R 1 is a protecting group which can be cleaved in an acidic medium, such as 2-tetrahydropyranyl or 1-ethoxy- + 2 ethyl, and M and R have the same meaning as above, the group r 1 is cleaved in an acidic medium. and the compounds of general formula (I) obtained are, if desired, converted into their salts, liberated from their salts or converted into other salts.

If M + denotes a cation, it is preferably an alkali metal cation, such as a sodium or potassium ion, or an alkaline earth ion, such as a calcium or magnesium ion or an ammonium ion.

When Y is halogen, it preferably represents a chlorine, bromine or iodine atom.

The methods according to the different method options are performed as follows:

When working according to process variant a), the reduction of the compounds of the general formula (II) is carried out expediently by catalytic hydrogenation. The catalyst used is preferably palladium, platinum or Raney nickel bound to a support, such as activated carbon. The hydrogenation is carried out in a solvent, preferably water, at room temperature or under heating, at normal pressure or at elevated pressure.

In process variant b) in the reaction of compounds of general formula (III) with compounds of general formula (IV), the same procedure is carried out at room temperature in the presence of a solvent, preferably water or dimethylformamide, however, the process can also be carried out without solvent in the molten state. In both cases, an acid scavenger is used, preferably an alkali metal hydroxide, carbonate or bicarbonate. As the component of general formula (IV), propanesulfon, 3-halo-1-propanesulfonic acid or their salts are suitably used.

According to process variant c), the protecting group is suitably cleaved in a hydrochloric acid medium.

The starting materials for the process alternatives described above can be prepared as follows: 5 61306

Compounds of general formula (II) are obtained by condensing compounds of general formula (VI) * CO-CH- rV 3 1 J (vn ho3s-ch2-ch2-ch2-o

OH

salts of the sulfonic acids of the general formula (VII)

B

’OR

° "ΧΧ,

With compounds according to Ok 2, wherein R and R have the same meaning as above. The condensation is carried out in an aqueous medium at room temperature in the presence of an alkali hydroxide, preferably sodium or potassium hydroxide. According to another method, compounds of formula (II) may be prepared by reacting compounds of general formula (VIII)

O

- -CC. Compounds of formula XX, 2 wherein R and R are as defined above for reaction with compounds of general formula (IV).

This reaction is carried out at room temperature in a solvent, suitably water, in the presence of an acid scavenger such as an alkali metal hydroxide, carbonate or bicarbonate.

Compounds of general formula (III) are obtained by reduction of compounds of general formula (VIII). The reduction is preferably carried out catalytically by hydrogenation in a solvent, preferably water, at room temperature or under heating.

Salts of the compounds of general formula (I) may be conveniently prepared by neutralizing the free acylphenoxypropanesulphonic acids with an oxide or hydroxide of the desired metal or with salts of the metal with a weak acid, preferably carbonates or bicarbonates. The salts thus obtained can be converted into salts with other metal ions by first forming sparingly soluble salts of the compounds of general formula (I), for example calcium salts, and then reacting these salts with the sulphate of the desired metal cation. The calcium sulphate formed is filtered off and the salt of the compound of general formula (I) is obtained by evaporating the filtrate or immediately crystallizing from the filtrate.

The following examples illustrate the preparation of the compounds of the invention.

Example 1 15.2 g of 2,4-dihydroxyacetophenone are suspended in 30 g of water, 10 g of sodium hydrogen carbonate are added to the suspension. The suspension is gently heated until a homogeneous solution is formed. The reaction mixture is cooled to 0 ° C, whereupon the acetophenone salt separates. With vigorous stirring, 6.8 g of 100% substance are added to the suspension, corresponding to propane sultenes. The reaction mixture is stirred at 0 ° C for 2 hours, then heated on a water bath for 15 minutes. If the solution is acidic, it is neutralized, then its pH is adjusted to 2 with a small amount of concentrated hydrochloric acid. Upon cooling to 0 ° C, the product separates.

It is filtered, washed with a small amount of ice water, dried, suspended in acetone, filtered again and dried again.

10.5 g (72%) of 2-hydroxy-4- (3-sulfopropyl-1-oxy) -acetophenone sodium are obtained. Melting point ^ 300 ° C.

Example 2 5.0 g of 2-hydroxy-3- (3-sulfopropyl-1-oxy) -acetophenone sodium and 2.6 g of isovaniline are stirred in 17 ml of 8N sodium hydroxide at room temperature for 48 hours. The yellow suspension is then acidified with 10% hydrochloric acid, the separated echo is filtered off, suspended in 50 ml of acetone, filtered off again with suction and then dried. 6.0 g (82%) of 2 ', 3-dihydroxy-4-methoxy-41- (3-sulfopropyl-1-oxy) chalcone sodium are obtained, melting at 237-276 ° C. If desired, the product can be further purified by recrystallization.

Example 3 14.4 g of 2-hydroxy-4- (3-sulfopropyl-1-oxy) -acetophenone sodium and 8.0 g of 3-hydroxy-4-ethoxybenzaldehyde are stirred at room temperature in 60 ml of 8N sodium hydroxide for 96 hours. . The yellow suspension is then acidified with 10% hydrochloric acid. The separated crude product is filtered off and recrystallized twice from water. No 6. 6.0 g (28%) of 21,3-dihydroxy-4-ethoxy-4 '- (3-sulfopropyl-1-oxy) -chalcone sodium are obtained, which begins to withdraw at 250 ° C but does not melt.

Example 4 5.0 g of 2 ', 3-dihydroxy-4-ethoxy-4' - (3-sulfopropyl-1-oxy) chalcone sodium are dissolved in 50 ml of water and hydrogenated in the presence of palladium on carbon (1 g) at 60 ° At C until the calculated amount of hydrogen is bound. The catalyst is filtered off from the solution, the filtrate is evaporated to dryness and the residue is crystallized twice from a small amount of water. 2.0 g (40%) of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-ethoxyphenyl) -propan-1-one are obtained, melting At 239-241 ° C (dec.).

Example 5 20 g of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-methoxyphenyl) -prop-2-en-1-one sodium are hydrogenated 100 in ml of water in the presence of palladium on carbon (4 g) at 60 ° C until the calculated amount of hydrogen is bound. The reaction mixture is then heated to 95 ° C, the catalyst is filtered off and the solution is cooled. The separated material is filtered off with suction, washed with a small amount of ice water and then dried. 13-14 g of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-methoxyphenyl) -propan-1-one are obtained, melting at 257- 258 ° C. Yield 65-70%.

Example 6

Palladium carbon is prehydrated in 50 ml of water, then 10 g of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-benzyloxy-4-methoxyphenyl) -prop-2 are added. en-l-one. The resulting suspension is hydrogenated at 60 ° C with stirring until 2 molar equivalents of hydrogen are bound. The catalyst is filtered off from the still warm solution. 7.0 g of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-methoxyphenyl) -propan-1-one are obtained from the cooled solution.

Example 7

Palladium carbon is prehydrated in 50 ml of water, then 10 g of 1- [2-hydroxy-4- (3-sulfo-1-propyl-1-oxy) -phenyl] -3- [3- (2-tetrahydropyranyloxy) - metoksifenyyli7-4-prop-2-en-l-one. The suspension is hydrogenated with stirring at 60 ° C until 1 molar equivalent of hydrogen is bound. The catalyst is filtered off, 1 ml of concentrated hydrochloric acid is added to the resulting solution, then heated at 90 ° C for 20 minutes. 6.5 g of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-methoxyphenyl) -propan-8 61306 1-one are obtained from the cooled solution.

Example 8 7.2 g of 1- (2,4-dihydroxyphenyl) -3- [3- (2-tetrahydropyranyloxy) -4-methoxyphenyl] r-propan-1-one are dissolved in 22 ml of 1-n-sodium hydroxide. 2.68 g of propane sultene are added portionwise to the solution at room temperature. The solution is then heated on a steam bath for 15 minutes, then 2 ml of concentrated hydrochloric acid are added and heated for a further 20 minutes. The solution is filtered to boiling. After cooling, 4.0 g of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-methoxyphenyl) -propan-1-one are obtained.

Example 9 The sodium salt of 1- [2-hydroxy-4- (3-sulfopropyl-1-oxy) -phenyl] -3- (3-hydroxy-4-methoxyphenyl) -propan-1-one is converted to other salts via the calcium salt . To the concentrated aqueous solution of the sodium salt is added, with excessive heating, the calcium chloride solution is filtered, the separated calcium salt is filtered, washed free of sodium and suspended in boiling water. An equivalent amount of the desired metal sulfate is added to the suspension. The suspension is stirred for about half an hour, then the separated calcium sulphate is filtered off and the solution is left to crystallize or, if necessary, evaporated to dryness.